Project Summary Specific genetic alterations in cancer cells may reprogram their metabolic networks and render them highly dependent on particular nutrients for survival. A mechanistic understanding of nutrient dependency in cancer cells has important implications for cancer treatment because drugs that impair nutrient metabolism may be effective for killing cancer cells that depend on specific nutrients for survival while sparing normal cells. While targeting nutrient dependency has been successful in leukemia, to date there has been limited success in targeting nutrient dependency in solid tumors. Therefore, there is a significant need to understand the mechanisms of action of anti-neoplastic agents that target nutrient dependency in cancer cells. SLC7A11 is an amino acid transporter that enables cystine uptake and its subsequent conversion to cysteine, which is critical for maintaining redox balance and cell survival. SLC7A11 is frequently overexpressed in human cancers, including KEAP1-mutant lung cancers. This application aims to determine the roles and mechanisms of SLC7A11 in regulating nutrient dependency and to therapeutically target nutrient dependency in cancers with aberrant expression of SLC7A11. Our specific aims are: Specific Aim 1: To determine the metabolic mechanisms underlying SLC7A11-induced glucose dependency in cancer cells. Specific Aim 2: To determine the therapeutic potential of inhibiting GLUTs or the PPP in treating tumors with aberrant SLC7A11 expression. The rationale for the proposed research is that studying the roles of SLC7A11 in regulating glucose dependency will not only advance our mechanistic understanding of nutrient dependency in cancer cells but also provide important insights into the development of novel therapeutic strategies to target metabolic vulnerabilities in SLC7A11- overexpressing tumors. Our proposed studies will have significant impact on both our understanding of the fundamental mechanisms of nutrient dependency and our ability to therapeutically target nutrient dependency in cancer treatment.